[unreadable] [unreadable] The many dendritic spines found on medium spiny neurons (MSNs) in the striatum are critical sites for synaptic integration of dopamine (DA) and glutamate input, which is essential for normal motor behavior. In advanced Parkinson's disease (PD) there is marked atrophy of dendrites and spines on MSNs (eg: McNeill et al., 1988). Similar pathology is observed in mice and rats with severe DA depletion (e.g.: Day et al, 2006). Importantly, a new mechanism involving dysregulation of intraspine Cav1.3 L-type Ca2+ channels has been found to account for spine loss following striatal DA depletion. Administration of the calcium channel antagonist nimodipine to rats, or the absence of these channels in transgenic mice prevents spine loss despite severe DA depletion (Day et al., 2006). The impact of altered dendritic morphology of MSNs in the parkinsonian striatum on efficacy and/or development of LIDs remains unclear. However, it would be anticipated that an absence of these critical input sites in the parkinsonian striatum would make it difficult for standard levodopa therapy to recapitulate normal physiological responses in the face of altered synaptic connectivity, and may lead to aberrant plasticity that results in development of levodopa-induced dyskinesias (LIDs). The proposed studies are aimed at testing the hypothesis that loss of dendritic spines on striatal MSNs is a key step intimately linked to the development of LIDs, and preventing spine loss will eliminate, or reduce development of LIDs. The design of these studies will also allow testing of two additional novel hypotheses: 1) aberrant synaptic remodeling in the striatum occurs following chronic levodopa and is a key feature underlying the development of LIDs; and 2) that reduction of MSN spine density plays a key role in classical basal ganglia motor deficits and decreased anti-parkinsonian drug responsiveness in severely parkinsonian subjects. To test the proposed hypotheses, we will examine the role that spine loss plays in development of abnormal dyskinetic movements and/or generalized motor deficits by comparing a battery of specific behavioral tests in severely DA depleted rats treated either with: 1) nimodipine to prevent spine loss, or 2) control vehicle which allows for typical dendritic spine loss. Quantitative and qualitative microscopic analyses of Golgi stained striatal MSNs will be examined and correlated with specific behaviors. Additionally, western blot analysis of the protein spinophilin/neurabin 2, a synaptic scaffolding protein highly enriched in dendritic spines will be examined to aid our understanding how changes in such structural proteins accompany morphological alterations in dendritic spine structure. Dyskinesias are a debilitating and costly side effect of therapy for many Parkinson's patients: The causes of these abnormal movements remain unknown. This proposal is designed to enhance our understanding of the intricate cellular processes underlying dyskinesias by studying the role of abnormal neuronal communication in their development. [unreadable] [unreadable] [unreadable]